1	CLIA Waiver Guidance Carol C. Benson¹ and Marina V. Kondratovich² ¹Associate Director, Division of Chemistry and Toxicology Devices, OIVD, CDRH, FDA ² Statistician, Division of Biostatistics, OSB, CDRH, FDA FDA- Industry Roundtable Meeting, May 11, 2006
2	CLIA Waiver Highlights Number of test systems categorized History of the path to CLIA waiver Consensus guidance – new thoughts on waiver approaches Next steps
3	Number of tests categorized – (2006 not complete)
4	History of the Path to Waiver Sept. 1995 CDC/CMS proposed rule Nov. 1997 FDA modernization act March 2001 FDA Draft Guidance Document (Not Implemented) Sept. 2005 FDA Draft Guidance Document
5	42 U.S.C. Section 263a(d)(3) “simple laboratory examinations and procedures that have been approved by the FDA for home use or that…are simple laboratory examinations and procedures that have an insignificant risk of an erroneous result”
6	42 U.S.C. Section 263a(d)(3) “including those that – (A) employ methodologies that are so simple and accurate as to render the likelihood of erroneous results by the user negligible, or (b) …pose no unreasonable risk of harm to the patient if performed incorrectly”
7	2005 Consensus Draft Guidance FDA interpretation law CLIAC, AdvaMed, CDC and CMS More flexible Scientifically based flex studies Emphasis on use of QC procedures Emphasis on intended users and patient specimens over time
8	Demonstrating “Simple” Fully automated instrument or unitized test system Uses direct unprocessed samples Non technique dependent specimen or reagent manipulation
9	Demonstrating “Simple” - 2 No operator intervention No technical or specialized training Clear labeling – PI with procedure steps at 7^th grade reading level Quick reference instructions at 7^th grade reading level
10	Demonstrating “Insignificant Risk of Erroneous Result” Tier 1 Hazard Analysis Tier 2 Fail-Safe and Failure Alert Mechanisms “Accuracy” - traceability
11	Tier 1: Hazard Analysis Operator error/human factors Specimen handling and integrity Reagent integrity Hardware, software and electronics integrity System stability Environmental factors
12	Tier 2 – Fail Safe and Failure Alert Mechanisms General recommendations in designing External quality control – stable and reproducible Validating Fail Safe/Failure Alert and ext controls – stress system
13	Flex Studies
14	Flex Studies - 2
15	Demonstrating “Insignificant Risk of Erroneous Result” - “Accuracy” The term “accurate” tests refers to those tests that are comparable to traceable methods. Prospective clinical studies of the device proposed for waiver: - intended clinical testing sites (3) - intended operators (9) - intended sample type and matrix whenever possible; - testing over time, as in typical intended use setting.
16	Demonstrating “Accuracy” The clinical studies should compare results obtained with the device proposed for CLIA Waiver (WM) to results obtained by Comparative Method (CM). The CM for the clinical study should be performed in laboratory setting by laboratory professionals.
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20	Demonstrating “Accuracy” -Quantitative Selection of Comparative Method (CM): Type A – Reference Method; Type B – Traceable method (measurement values with the same degree of trueness as reference method or reference materials; Type C – Traceable method (measurement values with small systematic bias, which may be clinically tolerable).
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30	Quantitative Performance Criteria Establish Allowable Total Error (ATE) (for 95% of differences for WM and CM): values of WM that fall within ATE zones are values that can be tolerated without invalidating the medical usefulness of the WM results. Establish Limits for Erroneous Results (LER) (no observations in LER): when WM values fall within LER zones, potential harm can occur to the patients if these results are utilized in medical decision making.
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34	Demonstrating “Accuracy” – Qualitative Study Design Selection of comparative method: type A – quantitative reference method; type B – quantitative traceable of type B; type C – quantitative traceable of type C; type D –qualitative reference method; type E – qualitative method which was tested by reference specimen panels (e.g, panels prepared by WHO, CDC, NIST).
35	Demonstrating “Accuracy” – Qualitative Study Design 3 or more clinical sites and intended users (9) 120 samples positive by CM 120 samples negative by CM Prospective patient samples, archival, contrived matrix-specific. Each sample split (or pair of samples): one part for test system (WM) and other part for comparator method (CM).
36	Demonstrating “Accuracy” – Qualitative Statistical Analysis Positive and negative agreements between WM and CM (95% two-sided CI) – for every site and combined
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43	Some Comments on Entire Guidance “…This is a tremendous guideline. One simple comment is that it could be envisioned to apply to all diagnostic assays, not just waiver assays.” “This draft Guidance must be withdrawn… The “accuracy” study for waiver should only be required to demonstrate that the waived user can operate the device as well as a professional user.” “Agreement studies” in 2001 FDA Guidance.
44	Plan Forward Draft guidance - solicit comments Revise draft to final guidance Issue proposed rule Issue final rule